EP2054062A1 - Utilisation d'inhibiteurs de l'hppd dans le traitement de la dépression et/ou des symptômes de sevrage associés aux drogues engendrant la dépendance - Google Patents

Utilisation d'inhibiteurs de l'hppd dans le traitement de la dépression et/ou des symptômes de sevrage associés aux drogues engendrant la dépendance

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Publication number
EP2054062A1
EP2054062A1 EP06779171A EP06779171A EP2054062A1 EP 2054062 A1 EP2054062 A1 EP 2054062A1 EP 06779171 A EP06779171 A EP 06779171A EP 06779171 A EP06779171 A EP 06779171A EP 2054062 A1 EP2054062 A1 EP 2054062A1
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EP
European Patent Office
Prior art keywords
compound
alkyl
group
animal
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06779171A
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German (de)
English (en)
Inventor
Kim Zachary Travis
John Posner
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Syngenta Ltd
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Syngenta Ltd
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Priority to EP09178767A priority Critical patent/EP2233136A1/fr
Publication of EP2054062A1 publication Critical patent/EP2054062A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to, inter alia, the use of a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor in the treatment of depression and/or the treatment of withdrawal symptoms associated with an addictive drug which causes dopamine dependent associative learning disorders. More specifically, the HPPD inhibitor is selected from the group consisting of: compound 1; compound 2; and compound 3.22.
  • HPPD 4-hydroxyphenylpyruvate dioxygenase
  • Clinical depression is a state of sadness, melancholia or despair that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living. Clinical depression is currently the leading cause of disability in the US as well as other countries, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization. • The effectiveness of antidepressants such as selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants per se is modest and there is a therapeutic need for more effective therapies
  • depression includes bipolar and unipolar disorders.
  • AU in all the present invention therefore seeks to provide, inter alia, a pharmaceutical for use in the treatment of depression which pharmaceutical overcomes and/or ameliorates the problems mentioned herein.
  • said medicament comprises a compound selected from the group consisting of: compound 1; 2; and 3.22 as disclosed herein.
  • said medicament comprises the compound depicted as compound 1.
  • the present invention still further provides the use as described above wherein said medicament comprises a selective serotonin reuptake inhibitor (SSRI) and/or a tricyclic antidepressant (tricyclic).
  • SSRI selective serotonin reuptake inhibitor
  • tricyclic tricyclic antidepressant
  • said SSRI is selected from the group consisting of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline or mixtures thereof and said tricyclic is selected from the group consisting of: amitriptyline, clomipramine, dosulepin, dothiepin, doxepin, maprotiline, mianserin, trazodone, trimipramine, amoxapine, imiprarnine, lofepramine, and nortriptyline or mixtures thereof.
  • said SSRI may be administered separately to the medicament comprising said HPPD inhibitor.
  • said tricyclic may be administered separately to the medicament comprising said HPPD inhibitor.
  • the present invention still further provides a kit comprising a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1; 2; and 3.22 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a selective serotonin reuptake inhibitor and/or a tricyclic antidepressant and a means for the delivery thereof to an animal.
  • the present invention still further provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a pharmaceutically effective amount of a compound selected from the group consisting of compound 1; 2; and 3.22 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a selective serotonin reuptake inhibitor and/or a tricyclic antidepressant together with a pharmaceutically acceptable diluent or carrier.
  • said SSRI is selected from the group consisting of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline or mixtures thereof and said tricyclic is selected from the group consisting of: amitriptyline, clomipramine, dosulepin dothiepin, doxepin, maprotiline, mianserin, trazodone, trimipramine, amoxapine, imipramine, lofepramine, and nortriptyline or mixtures thereof.
  • the present invention provides the use of HPPD inhibitors in the treatment of withdrawal symptoms associated with an addictive drug which causes dopamine dependent associative learning disorders.
  • addictive drugs include: psychostimulants like cocaine and amphetamine and also narcotic analgesics, opiate, nicotine, ethanol, tetrahydrocannabinol and phencyclidine.
  • Nicotine is a stimulant which temporarily improves alertness and memory, but also forms a strong physical and psychological chemical dependence (addiction). Through the use of cigarettes, cigars, and chewing tobacco, nicotine is one of the most heavily used addictive drugs. Medical research has determined that smoking is a major contributing factor towards many health problems, particularly lung cancer, emphysema, and cardiovascular disease.
  • the present invention provides for the use of a HPPD inhibitor to act as, inter alia, a stimulant to increase production of brain dopamine.
  • This stimulant effect will be exploited as an aid to achieving abstinence from tobacco containing products by reducing craving, lowering the brain reward-threshold and alleviating some nicotine withdrawal symptoms, which may include depressed mood, irritability, difficulty concentrating and increased appetite.
  • Cocaine is an example of another addictive drag.
  • Cocaine is a stimulant, creating what has been described as a "euphoric sense of happiness” and "increased energy”.
  • Cocaine can cause physical and psychological dependence, making withdrawal difficult.
  • Cocaine has become the second most widely used recreational drug in the U.S.
  • the invention provides, inter alia, the use a HPPD inhibitor to increase the brain concentration or turnover of dopamine, and so reduce the adverse symptoms of cocaine withdrawal, and increase the likelihood of successful withdrawal.
  • the present invention therefore also seeks to provide, inter alia, a pharmaceutical for use in the treatment of the withdrawal symptoms associated with an addictive drug which cause dopamine dependant associative learning disorders, which pharmaceutical overcomes and/or ameliorates the problems mentioned herein.
  • a pharmaceutical for use in the treatment of the withdrawal symptoms associated with an addictive drug which cause dopamine dependant associative learning disorders, which pharmaceutical overcomes and/or ameliorates the problems mentioned herein.
  • the present invention therefore provides the use of at least one compound capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal in the manufacture of a medicament for use in the treatment of the withdrawal symptoms associated with an addictive drug which causes dopamine dependant associative learning disorders in said animal.
  • said addictive drug is a drug selected from the group consisting of: cocaine, amphetamine, opiate, nicotine, ethanol, tetrahydrocannabinol and phencyclidine.
  • said drug is nicotine.
  • said drug is cocaine.
  • the present invention still further provides the use as described above wherein said medicament comprises a compound selected from the group depicted as compound 1; 2; and 3.22.
  • the present invention still further provides the use as described above wherein the medicament comprises a further compound which is also capable of inhibiting A- hydroxyphenylpyruvate dioxygenase (HPPD) in an animal.
  • HPPD A- hydroxyphenylpyruvate dioxygenase
  • the present invention still further provides the use as described above wherein said medicament comprises a nicotine replacement therapy.
  • nicotine replacement therapies are well known in the art and include gums, patches, tablets, dragees, sprays and inhalers.
  • the present invention still further provides the use as described above wherein said medicament comprises bupropion.
  • the present invention still further provides the use as described above wherein said medicament is used in conjunction with a nicotine replacement therapy.
  • the present invention still further provides the use as described above wherein said medicament is used in conjunction with bupropion.
  • said nicotine replacement therapy may be administered separately to the medicament comprising said HPPD inhibitor.
  • said buproprion may be administered separately to the medicament comprising said HPPD inhibitor.
  • the present invention provides a kit comprising a pharmaceutically effective amount of compound selected from the group consisting of: 1; 3.22; and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a nicotine replacement therapy and/or bupropion and a means for the delivery thereof to an animal.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1; 3.22; and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a nicotine replacement therapy and/or bupropion together with a pharmaceutically acceptable diluent or carrier.
  • the present invention still further provides a pharmaceutical composition as described above which is in a form suitable for oral or parenteral administration.
  • the present invention still further provides a pharmaceutical composition as described above which is in palatable form suitable for oral administration selected from the group consisting of: tablets; lozenges; hard capsules; aqueous suspensions; oily suspensions; emulsions; dispersible powders; dispersible granules; syrups and elixirs.
  • the present invention still further provides a pharmaceutical composition as described above which is intended for oral use and is in the form of hard or soft gelatin capsules.
  • the present invention still further provides a pharmaceutical composition as described above which is in a form suitable for parenteral administration.
  • compositions of such HPPD inhibitors for use in the invention may be in various conventional forms well know in the pharmaceutical art and which are especially adapted for pharmaceutical purposes that is for administration to man and other warm-blooded animals.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use will normally contain, for example, at least one or more colouring, sweetening, flavouring and/or preservative agents and may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin,
  • compositions for oral use may also be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as arachis oil, liquid paraffin or olive oil.
  • Suitable pharmaceutically acceptable excipients for use in tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p- hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as gelatin or starch
  • lubricating agents such as magnesium stearate, stearic acid or talc
  • preservative agents such as ethyl or propyl p- hydroxybenzoate, and anti-
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Aqueous suspensions will generally contain the active ingredient in finely powdered form together with one or more pharmaceutically acceptable suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono-oleate.
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl
  • Aqueous suspensions will also typically contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, normally together with a flavouring and/or sweetening agent (such as sucrose, saccharin or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, normally together with a flavouring and/or sweetening agent (such as sucrose, saccharin or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil
  • a mineral oil such as liquid paraffin
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • Additional pharmaceutically acceptable excipients such as sweetening, flavouring and colouring agents, will generally also be present.
  • compositions of the invention may also be in the form of oil- in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, or esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • naturally-occurring gums such as gum acacia or gum tragacanth
  • naturally-occurring phosphatides such as soya bean, lecithin
  • esters or partial esters derived from fatty acids and hexitol anhydrides for example sorbitan monooleate
  • condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain for example from O.Olmg to lOmg of active agent per Kg of bodyweight combined with an appropriate and convenient amount of excipients.
  • Dosage unit forms will generally contain about 0.1 mg to about 500 mg of an active ingredient.
  • a formulation comprising compound 2, for example, intended for oral administration to humans will generally contain for example from O.Olmg to lmg of active agent per Kg of bodyweight combined with an appropriate and convenient amount of excipients.
  • Dosage unit forms for a formulation comprising compound 2 will generally contain about 0.1 mg to about 100 mg of an active ingredient.
  • a composition according to the invention would be administered so that a dose of the HPPD inhibitor (or of an equivalent amount of a pharmaceutically acceptable salt thereof) is received which is generally in the range 0.00002 to 10 mg/kg/day, or 0.001 to 500 mg/day more specifically, 0.05-10mg/day and 0.1-5mg/day or 0.01 to 10 mg of active agent per Kg of bodyweight daily given if necessary in divided doses.
  • a composition according to the invention would be administered so that a dose of the HPPD inhibitor (or of an equivalent amount of a pharmaceutically acceptable salt thereof) is received which is generally in the range 0.0002 to 1 mg/kg/day, or 0.01 to 100 mg/day. More specifically, from between 0.05 to lOmg/day and 0.1 to 5mg/day or 0.01 to lmg of active agent per Kg of bodyweight daily given if necessary in divided doses. AU ranges throughout this specification are inclusive. For example from 0.01 to 100 includes the values 0.01 and 100.
  • the effects of administration of the HPPD inhibitor thereof may be monitored by standard clinical chemical and blood assays.
  • a method of treating and/or preventing depression comprising administering to an animal a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1; 2; and 3.22 or a composition as described above.
  • a method of treating an animal suffering from withdrawal symptoms resulting from addiction to a drug which is responsible for the development of dopamine dependant associative learning disorders in said animal comprising administering to said animal a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1; 3.22; and 2 or a composition as described above.
  • HPPD inhibitors that are applicable to the present invention include compounds of formula I (the term formula I may be interchanged with compound 1):
  • G is C or N wherein when G is N then only one of E and R 2 are present;
  • D is hydrogen or R 3 ;
  • E is hydrogen or R 4 ;
  • D and E together are C 2 -C 3 alkylene which can be mono- or poly-substituted by R 6 ;
  • A is Cj-Qalkylene which can be mono- or poly-substituted by R 5 ; or A may additionally be carbonyl, oxygen or -N-R 7 - when D and E are other than C 2 -C 3 alkylene;
  • Ri, R 2 , R 3 , R 4 , R 5 and R 6 are each independently of the others hydrogen, Ci-C 4 alkyl, phenyl, Ci-C 4 alkoxy, halogen, hydroxy, cyano, hydroxycarbonyl or Ci-
  • R 2 and R 4 together form a C 2 -C 4 alkylene chain which can be interrupted by oxygen and/or carbonyl and/or sulfur, with the proviso that the oxygen and sulfur atoms are separated by at least one methylene group;
  • R 7 is Ci-C 4 alkyl, alkoxycarbonyl or Ci-C 4 alkylcarbonyl
  • Ro 36 is hydroxy, 0 " M + , wherein M + is an alkali metal cation or ammonium cation, halogen, d-C ⁇ alkylsulfonyloxy, amino, C 1 -C 4 alkylthio, Ci-Ci 2 alkylsulfinyl, C 1 - C] 2 alkylsulfonyl, Ci-Ci 2 haloalkylthio, d-C ⁇ haloalkylsulfinyl, Ci-C ⁇ haloalkylsulfonyl, Ci-C 6 alkoxy-CrC 6 alkylthio, Ci-C 6 alkoxy-C 1 -C 6 alkylsulfmyl, Ci-Cealkoxy-Ci- C 6 alkylsulfonyl, C 3 -Ci 2 alkenylthio, C 3 -C 12 alkenylsulfmyl, C 3 -Ci 2 alkenylsul
  • R 036 is phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonylamino, phenylsulfonyloxy, benzoyloxy or benzoyl-d-C 6 alkoxy, wherein the phenyl groups can in turn be substituted one or more times by halogen, nitro, cyano, C 1 -C 4 alkyl, Q-
  • C 4 haloalkyl, Ci-C 4 alkoxy and/or Q-Qhaloalkoxy, or R 036 is a group Het 07 -thio, Hetos-sulfinyl, Heto 9 -sulfonyl, HCt O1O -(CO)O or Heto ⁇ -
  • Heto 7 , Het O8 , Het O9 , Hetoio and Heto ⁇ are each independently of the others a five- to ten- membered monocyclic or annellated bicyclic ring system which may be aromatic or partially saturated and may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and each ring system may contain not more than two oxygen atoms and not more than two sulfur atoms, and the ring system itself can be substituted by C 1 -
  • Ro37, Ro38, Ro39 > Ro4o, Ro4i, Ro42, R ⁇ 43, Ro44 and R 047 are each independently of the others hydrogen or Ci-C 6 alkyl; or Ro 37 and R 038 together or Ro 3 9 and Ro 40 together or Ro 4J and Ro 42 together or Ro 43 and R 044 together are pyrrolidino, piperidino, morpholino or thiomorpholino, which can be mono- or poly-substituted by methyl groups; or T is T 2
  • R 34 is hydrogen, C]-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -
  • C 4 alkynyl or benzyl it being possible for the phenyl group to be substituted one or more times by C]-C 6 alkyl, d-Cehaloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, halogen, cyano, hydroxy and/or nitro;
  • R 35 is hydrogen, C 1 -C 4 alkyl, d-C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 4 alkenyl, C 3 - C 4 alkynyl or benzyl, it being possible for the phenyl group to be substituted one or more times by Ci-C ⁇ alkyl, d-C ⁇ haloalkyl, Ci-C 6 alkoxy, d-C 6 haloalkoxy, halogen, cyano, hydroxy and/or nitro;
  • R 36 is hydroxy, 0 " M + , wherein M + is an alkali metal cation or ammonium cation, halogen, d-C ⁇ alkylsulfonyloxy, amino, d-C 4 alkylthio, d-Ci 2 alkylsulfinyl, C 1 - C ⁇ alkylsulfonyl, d-C 12 haloalkylthio, d-C ⁇ haloalkylsulf ⁇ nyl, Ci-C ⁇ haloalkylsulfonyl, Ci-Cealkoxy-d-Cealkylthio, Ci-Cealkoxy-d-Qalkylsulfinyl, d-C 6 alkoxy-d-d-
  • R 36 is phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonylamino, phenylsulfonyloxy, benzoyloxy or benzoyl-CrC ⁇ alkoxy, it being possible for the phenyl groups in turn to be substituted one or more times by halogen, nitro, cyano, d-C 4 alkyl, d-C 4 haloalkyl, Ci-C 4 alkoxy and/or d-C 4 haloalkoxy, or R 36 is a group Het 7 -thio, Het 8 -sulfmyl, Hetg-sulfonyl, Het ⁇ Q-(CO)O or Het ⁇ -N(R 47 ); wherein
  • Het 7 , Het 8 , Hetg, Het 10 and Het ⁇ are each independently of the others a five- to ten- membered monocyclic or annellated bicyclic ring system which may be aromatic or partially saturated and may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and each ring system may contain not more than two oxygen atoms and not more than two sulfur atoms, and the ring system itself can be substituted by C 1 - C 6 alkyl, Ci-C 6 haloalkyl, d-C 6 alkoxy, C]-C 6 haloalkoxy, d-C 6 alkylthio, Ci- C 6 alkylsulfinyl, d-C 6 alkylsulfonyl, di(Ci-C 4 alkyl)aminosulfonyl, di(Ci-C 4 alkyl)amino, halogen, cyano, nitro or by phenyl, and the substituents on the nitrogen
  • R37, R38 > R-39, RJ O , Ru 5 R42, Rtf * R44 and R 47 are each independently of the others hydrogen or d-C 6 alkyl; or R 37 and R 38 together or R 39 and R 40 together or Rn and R 42 together or R 43 and R 44 together are pyrrolidino, piperidino, mo ⁇ holino or thiomorpholino, which can be mono- or poly-substituted by methyl groups; or T is T 3
  • R 49 is Ci-C 4 alkyl, d-C 4 haloalkyl, C 3 -C 6 cycloalkyl or halo-substituted C 3 -C 6 cycloalkyl;
  • Z 0I is a chemical bond, S, SO or SO 2 ; or -CO 2 -
  • R 50 is hydrogen or d-C 3 alkylene which can be substituted by the following substituents: halogen, hydroxy, d-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 - C 6 alkoxy-d-C 6 alkoxy, d-C ⁇ alkoxy-d-Cealkoxy-d-Qalkoxy, (3-oxetanyl)-oxy, C 1 - C ⁇ alkyl-substituted (3-oxetanyl)-oxy, benzylthio, benzylsulfinyl, benzylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl or phenylsulfonyl, it being possible for the phenyl- and benzyl-containing groups in turn to be substituted by one or more Ci
  • R 045 is Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 3 -C 6 cycloalkyl or halo-substituted C 3 -C 6 cycloalkyl; and their pharmaceutically acceptable salts, isomers and enantiomers.
  • the compounds of formula I also include the salts which such compounds are able to form with amines, alkali metal and alkaline earth metal bases or quaternary ammonium bases.
  • alkali metal and alkaline earth metal hydroxides as salt formers special mention should be made of the hydroxides of lithium, sodium, potassium, magnesium and calcium, but especially the hydroxides of sodium and potassium.
  • amines suitable for ammonium salt formation include ammonia as well as primary, secondary and tertiary Q-Qsalkylamines, Ci-C 4 hydroxyalkylamines and C 2 -C 4 alkoxyalkylamines, for example methylamine, ethylamine, n-propylamine, isopropylamine, the four butylamine isomers, n-amylamine, isoamylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, pentadecylamine, hexadecylamine, heptadecylamine, octadecylamine, methylethylamine, methylisopropylamine, methylhexylamine, methylnonylamine, methylpentadecylamine, methyloctadecylamine, ethylbutyl
  • formula I also includes the enolised forms of formulae Ia, Ib, Ic and Id wherein M is hydrogen or a metal ion or an ammonium ion.
  • compounds of formula I may also contain asymmetric carbon atoms, for 10 example in the case of the carbon atom carrying R 1 , D and A, all stereoisomer ⁇ forms are also included.
  • the organic substituent Q may be an inert substituent of any desired structure, provided that the compounds of formula I retain their action as HPPD inhibitors in animals. Such tests of these compounds may be carried out in accordance with the 15 experimental methods described herein.
  • Q is preferably a mono- or poly-substituted phenyl, pyridyl or heteroaryl group, especially 2-benzoyl, 2-isonicotinoyl and 2-nicotinoyl derivatives, the substitution pattern of those groups being freely selectable provided that the compounds of formula I retain their action as HPPD inhibitors in animals.
  • Ai or A 2 are independently selected from methine, C(Ra 1 ) or N(O) P ; (wherein preferably at least one of Ai or A 2 is methine p is 0 or 1;
  • Ra 1 is hydrogen, d-C 6 alkyl, hydroxy, Ci-C 6 alkoxy, Cj-C ⁇ haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 haloalkenyloxy, C 3 -C 6 alkynyloxy, Ci-C 4 alkylcarbonyloxy, Ci-C 4 alkylsulfonyloxy, tosyloxy, Ci-C 4 alkylthio, C]-C 4 alkylsulfmyl, Ci-C 4 alkylsulfonyl, Ci-C 4 alkylamino, di- Ci-C 4 alkylamino, C]-C 4 alkoxycarbonyl, Ci-Qhaloalkyl, formyl, cyano, halogen, phenyl or phenoxy; it being possible for phenyl in turn to be substituted by Ci ⁇ C 3 alkyL Q- C 3 haloalkyl, Ci-C 3 alkoxy,
  • X 6 is a C]-C 6 alkylene, C 3 -C 6 alkenylene or C 3 -C 6 alkynylene chain which can be mono- or poly-substituted by halogen and/or by X 8 , the unsaturated bonds of the chain not being bonded directly to the substituent X 5 ;
  • Xg is hydroxy, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyloxy, Ci-C 6 alkoxy-Ci-C 6 alkoxy, Ci- C 6 alkoxy-Ci-C 6 alkoxy-Ci-C 6 alkoxy or C]-C 2 alkylsulfonyloxy;
  • X 5 is oxygen, -0(CO)-, -(CO)O-, -0(CO)O-, -N(Ci-C 4 alkyl)-O-, -O-N(C r C 4 alkyl)-, thio, sulfinyl, sulfonyl, -SO 2 N(C,-C 4 alkyl)-, -N(C r C 4 alkoxy)SO 2 -, -N(C,-C 4 alkyl)SO 2 -, -N(Ci-C 2 alkoxy-Ci-C 2 alkyl)SO 2 -
  • Ra 6 is hydrogen, C r C 4 alkyl, Ci-C 4 alkylthio-C 1 -C 4 carbonyl, C i-C 4 alkylsulfmyl-Ci- C 4 carbonyl, C 1 -C 4 alkylsulfonyl-C 1 -C 4 carbonyl, Q-Qalkoxycarbonyl, Cj-
  • Ra 2 is hydrogen, Ci-C 6 alkyl, Ci-C ⁇ haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, vinyl substituted by Ci-C 2 alkoxycarbonyl or by phenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, ethynyl substituted by trimethylsilyl, hydroxy, Ci-C 2 alkoxy, Ci-C 2 alkoxycarbonyl or by phenyl, C 3 -C 6 allenyl, C 3 -C 6 cycloalkyl, halo-substituted C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, Ci-C 6 haloalkoxy, C 3 -C 6 haloalkenyloxy, cyano-Ci- C 4 al
  • X 2 is a Ci-C ⁇ alkylene, C 3 -C 6 alkenylene or C 3 -C 6 alkynylene chain which can be mono- or poly-substituted by halogen or by X 4 , the unsaturated bonds of the chain not being bonded directly to the substituent X 1 ;
  • X 4 is hydroxy, d-C 6 alkoxy, C 3 -C 6 cycloalkyloxy, Ci-C 6 alkoxy-Ci-C 6 alkoxy, Ci- C 6 alkoxy-Ci-C 6 alkoxy-Ci-C 6 alkoxy or Ci-C 2 alkylsulfonyloxy;
  • Xi is oxygen, -O(CO)-, -(CO)O-, -0(CO)O-, -N(Ci-C 4 alkyl)-O-, -O-N(Ci-C 4 alkyl)-, thio, sulfmyl, sulfonyl, -SO 2 N(C, -C 4 alkyl)-, -N(d-C 4 alkyl)SO 2 -, -N(Ci-C 2 alkoxy-d- C 2 alkyl)SO 2 - or-N(d-C 4 alkyl)-;
  • X 3 and X 7 are each independently of the other a Ci-C 8 alkyl, C 3 -C 6 alkenyl or C 3 - C 6 alkynyl group which is mono- or poly-substituted by the following substituents: halogen, hydroxy, amino, formyl, nitro, cyano, mercapto, carbamoy
  • phenyl- or benzyl-containing groups in turn to be substituted by one or more C ⁇ -C 6 alkyl, Ci-C 6 haloalkyl, d-C 6 alkoxy, d-C 6 haloalkoxy, halogen, cyano, hydroxy and/or nitro groups, or
  • X 3 and X 7 are each independently of the other phenyl which can be substituted one or more times by C 1 -QaUCyI, C ! -C 6 haloalkyl, d-C 6 alkoxy, d-C 6 haloalkoxy, halogen, cyano, hydroxy and/or nitro; or
  • X 3 and X 7 are each independently of the other C 3 -C 6 cycloalkyl, d-C 6 alkoxy- or C 1 - C 6 alkyl-substituted C 3 -C 6 cycloalkyl, 3-oxetanyl or Ci-C 6 alkyl-substituted 3-oxetanyl; or X 3 and X 7 are each independently of the other a five- to ten-membered monocyclic or annellated bicyclic ring system which may be aromatic or saturated or partially saturated and may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, the ring system being bonded to the substituent X 1 or X 5 directly or by way of a C 1 - C 4 alkylene, C 2 -C 4 alkenyl-C 1 -C 4 alkylene, C 2 -C 4 alkynyl-Ci-C 4 alkylene, -N(Ci-C 4 alkyl)- Ci-C 4
  • -C 6 haloalkyl C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, Ci-C 6 alkoxy, hydroxy, Ci-C 6 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, mercapto, d-C 6 alkylthio, C 1 - Qhaloalkylthio, C 3 -C 6 alkenylthio, C 3 -C 6 haloalkenylthio, Cs-C ⁇ alkynylthio, C 2 - C 5 alkoxyalkylthio, C 3 -C 5 acetylalkylthio, Cs-C ⁇ alkoxycarbonylalkylthio, C 2 -C 4 - cyanoalkylthio, d-C ⁇ alky
  • Ra 4 is hydrogen, d-C 6 alkyl, hydroxy, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 haloalkenyloxy, C 3 -C 6 alkynyloxy, Ci-C 4 alkylcarbonyloxy, Ci-C 4 alkylsulfonyloxy, tosyloxy, Ci-C 4 alkylthio, Ci-C 4 alkylsulfinyl, d-C 4 alkylsulfonyl, C 1 -C 4 alkylamino, di- C 1 -C 4 alkylamino, d-C 4 alkoxycarbonyl, Ci-C 4 haloalkyl, formyl, cyano, halogen, phenyl or phenoxy, it being possible for phenyl in turn to be substituted by Ci-C 3 alkyl, C 1 - C 3 haloalkyl,
  • Ra 5 is hydrogen, d-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 - C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, d-C 6 haloalkoxy, Ci- C 6 alkylthio, d-C 6 alkylsulfmyl, Ci-C 6 alkylsulfonyl, Ci-C 6 haloalkylthio, C 1 - C 6 haloalkylsulf ⁇ nyl, d-C 6 haloalkylsulfonyl, Ci-C 6 alkylamino, di-C 2 -C 6 alkylamino, C 1 - C 6 alkylaminosulfonyl, di-C 2 -C 6 alkylaminosul
  • alkyl groups appearing in the above substituent definitions may be straight- chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl or tert-butyl.
  • Alkoxy, alkenyl and alkynyl radicals are derived from the mentioned alkyl radicals.
  • the alkenyl and alkynyl groups may be mono- or polyunsaturated.
  • Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • Alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, iso- butoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; preferably methoxycarbonyl or ethoxycarbonyl.
  • Halogen is generally fluorine, chlorine, bromine or iodine. The same is also true of halogen in conjunction with other meanings, such as haloalkyl or halophenyl.
  • Haloalkyl groups having a chain length of from 1 to 6 carbon atoms are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2- fluoroprop-2-yl, pentafluoroethyl, l,l-difluoro-2,2,2-trichloroethyl, 2,2,3,3- tetrafluoroethyl and 2,2,2-trichloroethyl, pentafluoroethyl, heptafluoro-n-propyl and perfluoro-n-hexyl.
  • Alkenyl and alkynyl groups can be mono- or poly-unsaturated, so that alkyl, alkenyl and alkynyl chains having one or more double or triple bonds are also included.
  • An alkylene chain can also be substituted by one or more Ci-C 3 alkyl groups, especially by methyl groups. Such alkylene chains and alkylene groups are preferably unsubstituted. The same applies also to all groups containing C 3 -C 6 cycloalkyl, C 3 - C 5 oxacycloalkyl, C 3 -C 5 thiacycloalkyl, C 3 -C 4 dioxacycloalkyl, C 3 -C 4 dithiacycloalkyl or C 3 -C 4 oxathiacycloalkyl which occur, for example, also as part of oxygen- and sulfur- containing heterocyclic ring systems of the radicals Rai and Ra 2 .
  • each R 26 is methyl
  • each R 27 independently is hydrogen, Ci-C 3 alkyl, d-C 3 alkoxy, d-C 3 alkylthio or trifluoromethyl
  • X 9 is oxygen or sulfur.
  • R 46 is hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 alkylthio;
  • R 47 is hydrogen, halogen, Q-Qalkyl or C r C 4 alkoxy;
  • R 50 , R51, R52, R53, R54, R 55 , R 56 , R 57 , R 58 and R 5 g are hydrogen or Ci-C 4 alkyl; and
  • Xi 0 is oxygen or NOR 59 .
  • R 1 and R 2 are hydrogen; A is Ci-C 2 alkylene; D and E together are C 2 -C 3 alkylene; Q is Q 1 , wherein
  • p is O;
  • Raj is hydrogen, d-C 6 alkyl, hydroxy, Ci-C 6 alkoxy, d-C 6 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 haloalkenyloxy, C 3 -Cealkynyloxy, Ci-C 4 alkylcarbonyloxy, Ci-C 4 alkylsulfonyloxy, tosyloxy, d-C 4 alkylthio, C 1 -C 4 alkylsulfinyl, Ci-C 4 alkylsulfonyl, C 1 -C 4 alkylamino, di- Ci-C 4 alkylamino, Ci-C 4 alkoxycarbonyl, d-C 4 haloalkyl, formyl, cyano, halogen, pheny
  • Ra 2 is hydrogen, Ci-C 6 alkyl, d-C ⁇ haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, vinyl substituted by C t -C 2 alkoxycarbonyl or by phenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, ethynyl substituted by trimethylsilyl, hydroxy, d-C 2 alkoxy, C]-C 2 alkoxycarbonyl or by phenyl, C 3 -C 6 allenyl, C 3 -C 6 cycloalkyl, halo-substituted C 3 -C 6 cycloalkyl, d-C 6 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, d-C ⁇ haloalkoxy, C 3 -C 6 haloalkenyloxy
  • Ra 3 and Ra 4 are hydrogen and Ras is as defined above.
  • Q is Qi
  • Ra 3 and Ra 4 are hydrogen
  • Ras is Ci-C 3 haloalkyl, especially trifluoromethyl
  • Ra 2 is Ci-C 4 alkoxy-C 1 -C 4 alkoxy-C 1 -C 4 alkyl, especially methoxyethoxymethyl.
  • HPPD inhibiting compounds are well known in the art and there are numerous tests that can be employed to identify the capacity of a test compound to inhibit HPPD.
  • in vitro screening assays as described in the examples of the present application may be use or alternative in vitro screening methods can be employed such as the method described in example 11 of WO02/46387 wherein a known HPPD enzyme is selected and a test inhibitor compound is applied.
  • the HPPD inhibitor is 2-(2-Nitro-4- Trifluoromethylbenzoyl)-1,3-Cyclohexanedione (compound 2).
  • compound 2 may be interchanged with formula II). It will be appreciated that 2-(2-Nitro-4- Trifluoromethylbenzoyl)-1 ,3-Cyclohexanedione (compound 2) may exist in one or more tautomeric forms, one of which is shown in formula (II) (i.e. compound 2) : and which forms are readily inter-convertible by keto-enol tautomerism.
  • the invention includes the use of 2-(2-Nitro-4- Trifluoromethylbenzoyl)-1,3-Cyclohexanedione in any of such tautomeric forms or as a mixture thereof.
  • 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexanedione is acidic and readily forms salts with a wide variety of bases.
  • Particularly suitable salts of 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3- Cyclohexanedione suitable for use as active ingredients in pharmaceutical compositions according to the invention include, for example, pharmaceutically acceptable base- addition salts, for example, alkali metal (such as potassium or sodium), alkaline earth metal (such as calcium or magnesium) and ammonium salts, and salts with organic bases giving physiologically acceptable cations (such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine).
  • 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexanedione may be obtained by conventional procedures of organic chemistry already known for the production of structurally analogous materials.
  • 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexanedione may be conveniently obtained by reaction of 2-nitro-4-trifluoromethylbenzoyl chloride with cyclohexane-l,3-dione in the presence of acetone cyanhydrin and a suitable base such as triethylamine. .
  • the starting 2-nitro-4-trifluoromethylbenzoyl chloride may itself be obtained from the corresponding benzoic acid, for example by reaction with thionyl chloride or oxalyl chloride as is described in Reagents for Organic Synthesis, (J Wiley and Sons, 1967; editors: Fieser L. F. and Fieser M.; VoI 1, pp. 767-769) and is generally used without special purification.
  • 2-nitro-4-trifluroromethylbenzoic acid may be obtained, for example, as described by Haupstein et al. in J. Amer. Chem. Soc, 1954, 76, 1051, or by one of the general methods well known to the skilled person.
  • the HPPD inhibitor or precursor is a compound having the structure depicted in Table A below. Table A.
  • HPPD inhibitor includes those compounds which are capable of inhibiting HPPD in animals and any precursor compound thereof which is capable of being metabolised in the animal to produce the HPPD inhibiting compound.
  • tyrosine catabolism pathway may be inhibited in addition to or as an alternative to the inhibition of HPPD.
  • inhibitors of enzymes/compounds that are "upstream" of HPPD in said pathway such as tyrosine aminotransferase
  • inhibitors of enzymes/compounds "downstream" of HPPD in said pathway such as homogentisic acid oxidase may also be used.
  • the present invention still further provides the use as described above wherein said medicament is administered in combination with an anti-inflammatory agent.
  • the present invention still further provides the use as described above wherein said medicament comprises an anti-inflammatory agent.
  • the present invention still further provides the use as described above wherein said medicament comprises a first HPPD inhibitor and a further HPPD inhibitor and wherein said first inhibitor is different from said further inhibitor and wherein said inhibitors are present in amount to treat and/or prevent depression and/or treat the withdrawal symptoms in an animal associated with an addictive drug which causes dopamine dependant associative learning disorders in said animal.
  • said first and further HPPD inhibitor is selected from an inhibitor described above.
  • said first and/or second compound comprises a precursor compound.
  • kits comprising a pharmaceutically effective amount of a first HPPD inhibitor and a further HPPD inhibitor and wherein said first inhibitor is different from said further inhibitor.
  • said first and further HPPD inhibitor is selected from an inhibitor described above and wherein said inhibitors are present in amount to treat and/or prevent depression and/or treat the withdrawal symptoms in an animal associated with an addictive drug which causes dopamine dependant associative learning disorders in said animal.
  • said first inhibitor comprises 2-(2-Nitro-4-
  • Trifluoromethylbenzoyl)-1,3-Cyclohexanedione (compound 2).
  • said first inhibitor comprises the compound depicted as 3.22 as described above.
  • Figure 1 is a representation of part of a pathway indicating the metabolism of tyrosine.
  • mice were dosed orally with 0.1 mg/Kg of 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-
  • mice were orally dosed with the dosing vehicle.
  • mice dosed with 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-
  • Cyclohexanedione had elevated levels of plasma tyrosine.
  • dopamine was increased by up to 16% and dopamine turnover was increased by up to 27% when compared with the mean of the controls.
  • mice were dosed orally with 0.1 mg/Kg of 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3- Cyclohexanedione.
  • mice were orally dosed with the dosing vehicle. After 6 hours, plasma tyrosine levels were identified. Dopamine levels and dopamine turnover were also analysed. The results yielded mice dosed with 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3- Cyclohexanedione had elevated levels of plasma tyrosine.
  • dopamine was increased by up to 15% and dopamine turnover was increased by up to 15% when compared with the mean of the controls.
  • dopamine turnover was increased by 25% in the treated compared with the control group.
  • noradrenaline was increased by up to 76% and 21% in the treated rats cortex and hypothalamus when compared with the mean of the controls.
  • Example 4 Analysis of stimulatory effect of HPPD inhibitors as a mechanism for the treatment of withdrawal symptoms associated with an addictive drug such as nicotine.
  • 12 rats were dosed orally with 2 mg/Kg of 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3- Cyclohexanedione.
  • 12 rats were orally dosed with the dosing vehicle.

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Abstract

La présente invention concerne, entre autres, l'utilisation d'un composé pouvant inhiber la 4-hydroxyphénylpyruvate dioxygénase (HPPD) chez un animal dans la fabrication d'un médicament destiné à être utilisé dans le traitement et/ou la prévention de la dépression. L'invention concerne également l'utilisation d'un composé pouvant inhiber l'HPPD chez un animal dans la fabrication d'un médicament destiné à être utilisé dans le traitement des symptômes de sevrage associés à une drogue engendrant la dépendance qui provoque des troubles d'apprentissage associatif dépendants de la dopamine chez ledit animal. Dans un mode de réalisation, ledit inhibiteur de l'HPPD est choisi dans le groupe constitué par le composé indiqué comme étant le composé 1; 2; et 3.22.
EP06779171A 2006-08-18 2006-08-18 Utilisation d'inhibiteurs de l'hppd dans le traitement de la dépression et/ou des symptômes de sevrage associés aux drogues engendrant la dépendance Withdrawn EP2054062A1 (fr)

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EP06779171A Withdrawn EP2054062A1 (fr) 2006-08-18 2006-08-18 Utilisation d'inhibiteurs de l'hppd dans le traitement de la dépression et/ou des symptômes de sevrage associés aux drogues engendrant la dépendance

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US (1) US20100305095A1 (fr)
EP (2) EP2233136A1 (fr)
JP (1) JP2010501532A (fr)
CN (1) CN101500566A (fr)
AU (1) AU2006347397A1 (fr)
BR (1) BRPI0621959A2 (fr)
CA (1) CA2659424A1 (fr)
IL (1) IL196367A0 (fr)
MX (1) MX2009001710A (fr)
NZ (1) NZ574153A (fr)
WO (1) WO2008020150A1 (fr)

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GB0504103D0 (en) * 2005-02-28 2005-04-06 Syngenta Ltd Novel method
GB0814466D0 (en) * 2008-08-07 2008-09-10 Rosemont Pharmaceuticals Ltd Sertraline composition
WO2010054273A1 (fr) * 2008-11-06 2010-05-14 Synosia Therapeutics Traitement du syndrome des jambes sans repos et autres troubles du sommeil
PL2723320T3 (pl) 2011-06-23 2016-06-30 Swedish Orphan Biovitrum Int Ab Ciekła kompozycja farmaceutyczna zawierająca nityzynon
JP2017505804A (ja) 2014-02-14 2017-02-23 インセプション ２、 インコーポレイテッド ピラゾロン化合物およびその使用

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JPS58501117A (ja) * 1981-07-15 1983-07-14 ワ−トマン，リチヤ−ド　ジエイ． 正常なひと患者における精神賦活剤
US4843071A (en) * 1986-12-05 1989-06-27 Serotonin Industries Of Charleston Method and composition for treating obesity, drug abuse, and narcolepsy
JP3130935B2 (ja) * 1991-06-24 2001-01-31 ゼネカ リミテッド 医薬組成物
CA2483159C (fr) * 2002-04-26 2010-08-10 Eli Lilly And Company Derives de triazole en tant qu'antagonistes des recepteurs de la tachykinine

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Title
See references of WO2008020150A1 *

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Publication number Publication date
JP2010501532A (ja) 2010-01-21
CN101500566A (zh) 2009-08-05
CA2659424A1 (fr) 2008-02-21
AU2006347397A1 (en) 2008-02-21
WO2008020150A1 (fr) 2008-02-21
EP2233136A1 (fr) 2010-09-29
MX2009001710A (es) 2009-02-25
NZ574153A (en) 2011-12-22
IL196367A0 (en) 2009-09-22
BRPI0621959A2 (pt) 2011-12-27
US20100305095A1 (en) 2010-12-02

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